[Show abstract][Hide abstract] ABSTRACT: The acute phase response (APR) is characterized by alterations in lipid and glucose metabolism leading to an increased delivery of energy substrates. In adipocytes, there is a coordinated decrease in Free Fatty acids (FFAs) and glucose storage, in addition to an increase in FFAs mobilization. Serum Amyloid A (SAA) is an acute phase protein mainly associated with High Density Lipoproteins (HDL). We hypothesized that enrichment of HDL with SAA, during the APR, could be implicated in the metabolic changes occurring in adipocytes.
In vitro differentiated human adipocytes (hMADS) were treated with SAA enriched HDL or recombinant SAA and the metabolic phenotype of the cells analyzed. In hMADS, SAA induces an increased lipolysis through an ERK dependent pathway. At the molecular level, SAA represses PPARγ2, C/EBPα and SREBP-1c gene expression, three transcription factors involved in adipocyte differentiation or lipid synthesis. In addition, the activation of the NF-κB pathway by SAA leads to the induction of pro-inflammatory cytokines and chemokines, as in the case of immune cells. These latter findings were replicated in freshly isolated mature human adipocytes.
Besides its well-characterized role in cholesterol metabolism, SAA has direct metabolic effects on human adipocytes. These metabolic changes could be at least partly responsible for alterations of adipocyte metabolism observed during the APR as well as during pathophysiological conditions such as obesity and conditions leading to insulin resistant states.
PLoS ONE 04/2012; 7(4):e34031. DOI:10.1371/journal.pone.0034031 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute phase serum amyloid A (A-SAA) is secreted by hepatocytes in response to injury and is regulated by proinflammatory cytokines. In obese humans, adipocytes are also a major contributor to circulating A-SAA levels.
We aimed to investigate the role and regulation of A-SAA in human adipose tissue (AT).
An approach combining microarrays and the FunNet bioinformatics tool was applied to human AT fractions (i.e. adipocytes vs. stroma vascular fraction) to hypothesize genes and functions related to A-SAA. Experiments with human AT from 37 obese subjects and human multipotent adipose-derived stem (hMADS) cells were used to confirm the microarray driven hypotheses.
Microarray analysis highlighted the relationship between A-SAA and stroma vascular fraction inflammatory genes, and between A-SAA and adipocyte-expressed ATP-binding cassette (ABC) transporters. We confirmed that serum amyloid A (SAA) protein is expressed in sc AT of obese subjects (n = 37, body mass index = 49.3 +/- 1.5 kg/m(2)) and showed that SAA protein expression correlated with adipocyte size (R = 0.44; P = 6.10(-3)), macrophage infiltration (R = 0.61; P = 10(-4)), and ABC subfamily A1 protein expression (R = 0.43; P = 9.10(-3)). IL-1beta, TNF-alpha, and human AT macrophage-conditioned medium significantly induced A-SAA secretion (from 2.6 to 7.6 fold) in hMADS cells. Recombinant SAA induced cholesterol ABC subfamily A1-dependent efflux from hMADS adipocytes by 4.3-fold in a dose-dependent manner.
This work provides original insight suggesting that A-SAA is a player in the dialogue between hypertrophied adipocytes and macrophages through its regulation of adipocyte cholesterol efflux.
The Journal of Clinical Endocrinology and Metabolism 03/2009; 94(5):1810-7. DOI:10.1210/jc.2008-2040 · 6.21 Impact Factor